Nucleic acid ligands which bind protein are known to those skilled in the art through Patent Cooperation Treaty International Publication No. WO91/19813 which was published on Dec. 26, 1991, the related U.S. Pat. No. 5,270,163, and other publications with related disclosures such as Tuerk, C. and Gold, L., Science 249, 505-510 (1990), Irvine, D. et al., J. Mol. Biol. 222, 739-761 (1991), and Tuerk, C. et al., Proc. Natl. Acad. Sci. USA 89, 6988-6992 (1992). Nucleic acid ligands are defined as nucleic acid molecules, each having a unique sequence, each of which has the property of binding specifically to a desired target compound or/molecule. The nucleic acid ligands have sufficient capacity for forming a variety of two- and three-dimensional structures and sufficient chemical versatility available within their monomers to act as ligands (form specific binding pairs) with virtually any chemical compound, whether monomeric or polymeric. The nucleic acid ligands may be made up of double or single stranded RNA or DNA and there may be more than one ligand for a given target. However, the ligands generally differ from one another in their binding affinities for the target molecule.
The nucleic acid ligands have structures or motifs that have been shown to be most commonly involved in non-Watson-Crick type interactions. Included among these structures or motifs are hairpin loops, symmetric and asymmetric bulges, pseudoknots, guanosine quadraplexes (or G-tetrads) and combinations thereof.
Also known in the art are reverse polarity sequences. For example, parallel stranded DNA has been synthesized in the form of hairpins with four-nucleotide central loops (consisting of either C or G) as described by van de Sande, J. H. et al., Science 241, 551 (1988). Also, the third oligodeoxyribonucleotide used in triple helix formation has its polarity reversed at about its midpoint as described by Horne, D. A. and Dervan, P. B., J. Am. Chem. Soc. 112, 2435 (1990) and PCT International Publication No. WO 91/06626. Furthermore, an oligonucleotide produced by the inversion of its 3' terminal linkage to yield a 3'-3' linkage and two 5' ends has shown increased stability to degradation in cell culture and serum. Shaw, J. et al., Nuc. Acids Res. 19, 747 (1991).